JPC SYSTEMIC PATHOLOGY

REPRODUCTIVE SYSTEM

January 2025

R-N15

 

SLIDE A: Signalment (JPC #4151819-00): Golden retriever

 

HISTORY: Subcutaneous mass from medial aspect of mammary gland 

 

HISTOPATHOLOGIC DESCRIPTION: Mammary gland: Expanding and effacing this section of tissue, compressing adjacent mammary glands is an unencapsulated, multilobular, well circumscribed, moderately cellular neoplasm composed of two distinct populations of cells with multifocal areas of osseous and cartilaginous metaplasia, on a dense, collagenous, occasionally sclerotic, stroma. The first population of cells are polygonal and arranged in variably sized and shaped cords, islands, and tubules with intratubular papillary projections. Tubule lumina often contain pink, homogenous secretory product or amphophilic to basophilic mucinous material. These neoplastic polygonal cells have indistinct cell borders, a moderate amount of eosinophilic cytoplasm, and round to oval nuclei with finely stippled chromatin and 1-3 distinct nucleoli. Anisocytosis and anisokaryosis are mild to moderate and there are <1 mitotic figures per 2.37mm². The second population of cells are spindle myoepithelial cells arranged in loose streams on a myxomatous stroma that have indistinct cell borders, a scant to moderate amount of eosinophilic cytoplasm, and oval to elongate nuclei with finely stippled chromatin and indistinct nucleoli. Mitotic figures are <1 per 2.37mm². Anisocytosis and anisokaryosis are mild. There is occasional single cell necrosis with hypereosinophilic cytoplasm and dense, pyknotic nuclei as well as multifocal loss of cellular architecture with replacement by eosinophilic cellular and karyorrhectic debris (lytic necrosis). Foci of bone contain adipose and hematopoietic elements (bone marrow) interspersed between bony trabeculae. There are moderate numbers of perivascular lymphocytes and plasma cells at the periphery of the neoplasm. 

 

MORPHOLOGIC DIAGNOSIS: Mammary gland: Benign mixed mammary tumor, golden retriever, canine.

 

SLIDE B: Signalment (JPC #3049000): An 8-year-old female spayed Belgian shepherd

 

HISTORY: Tissue from the right-side, fourth and fifth mammary glands 

 

HISTOPATHOLOGIC DESCRIPTION: Haired skin, mammary gland: Expanding the subcutis and infiltrating the surrounding adipose and mammary tissue is a partially encapsulated, multilobulated, well-demarcated, moderately cellular neoplasm composed of polygonal cells arranged in islands and trabeculae on a fine to moderate fibrovascular stroma. Neoplastic cells have distinct cells borders with moderate to abundant amount of eosinophilic cytoplasm containing numerous small vacuoles or a single large, discrete, clear vacuole (lipid) that frequently peripheralizes the nucleus. Nuclei are round to oval with coarsely stippled chromatin and 1 variably distinct nucleolus, or are flattened and hyperchromatic. Anisocytosis and anisokaryosis are moderate and the mitotic count is 1 per 2.37mm². Islands of neoplastic cells are separated and surrounded by thick bands of fibrous connective tissue. Multifocally, neoplastic cells are within blood and lymphatic vessels. Scattered throughout the neoplasm are aggregates of lymphocytes, plasma cells, and fewer neutrophils, occasionally admixed with necrotic debris and areas of hemorrhage, fibrin, and edema with few hemosiderin-laden macrophages.

 

Mammary lymph node: The subcapsular, parafollicular and medullary sinuses contain increased numbers of histiocytes that contain either intracytoplasmic brown globular pigment (hemosiderin) or intracytoplasmic erythrocytes (erythrophagocytosis). 

 

MORPHOLOGIC DIAGNOSIS: 

1. Haired skin, right fourth and fifth mammae (per contributor): Lipid-rich carcinoma, Belgian shepherd, canine.

2. Mammary lymph node: Sinus histiocytosis, chronic, diffuse, moderate with erythrophagocytosis and chronic hemorrhage. 

 

GENERAL DISCUSSION:

Benign mixed tumor

• One of the most common mammary neoplasms in dogs
• Mammary neoplasms containing both epithelial and myoeptihelial components are characterized as complex 
• Mixed tumors are complex tumors which also contain a mesenchymal component (ie. cartilage, bone, or adipose)
• Benign mixed tumors lack features of malignancy in both the epithelial and myoepithelial cells
• Malignant forms of mixed mammary neoplasms include carcinoma arising in benign mixed tumor and mixed carcinoma 

Lipid-rich carcinoma

• Lipid-rich carcinoma is a rare neoplasm of the mammary gland in dogs; there is one report of this neoplasm in a cat and one report in a Djungarian hamster
• Definitive diagnosis requires demonstration of lipid droplets in tumor cells with special histochemical stains (e.g. Oil Red O stain) or by electron microscopy
• May be found in younger intact bitches

 

PATHOGENESIS:

Benign mixed tumor

Lipid-rich carcinoma

• Often recur locally following surgical removal
• Can metastasize to local lymph nodes, bone marrow, lungs, endometrium, and the adrenal medulla

 

TYPICAL GROSS FINDINGS:

Benign mixed tumor

 

Lipid-rich carcinoma

• Single or multiple masses, well-circumscribed, yellow to grey, variably sized
• Small areas of hemorrhage and necrosis are often present in the neoplasm

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

Benign mixed tumor

• Well circumscribed neoplasm with epithelial, myoepithelial, and mesenchymal components
• A recent study reported a case with well-differentiated hepatoid gland-like cells in multiple nests around the periphery of the neoplasm and were immunologically similar to hepatoid gland cells (Otsuka et al, J Comp Pathol, 2022)
• Epithelial cell population is arranged in tubules or tubulopapillae 
• Myoepithelial cells are spindle to stellate and arranged in loose streams often on a myxomatous stroma
• There is only mild anisocytosis and anisokaryosis, the mitotic rate is low in both cell populations, and there is no evidence of local or lymphatic invasion
• The mesenchymal component varies in type (cartilage, muscle, fat) and amount

 

Lipid-rich carcinoma

• Solid nest and cords of atypical round to polygonal cells with distinct cell borders
• Moderate amount of cytoplasm with numerous small intracytoplasmic vacuoles 
• or a single large vacuole
• Nuclei are round to oval, vesicular, with clumped chromatin and 1-2 nucleoli
• Anisocytosis and anisokaryosis are moderate to marked
• Variable mitotic rate
• Lymph node metastasis and lymphatic invasion are common

 

ADDITIONAL DIAGNOSTIC TESTS:

Benign mixed tumor: 

• Sheets and clusters of moderate to large aggregates of uniform epithelial cells are typical of benign mammary tumors 
• Benign complex and mixed neoplasms will have individual or aggregates of spindle cells that may appear as free oval nuclei
• May have cartilage or bone elements (e.g. osteoblasts, osteoclasts, hematopoietic cells, or bright pink matrix (osteoid/chondroid)
• Diagnosis of mixed neoplasm with cytology can be difficult because low exfoliation of spindle cells or failure to sample mesenchymal components commonly occurs

Lipid-rich carcinoma

• Cytology: 
  1. For carcinomas in general, sheets and clusters of epithelial cells are expected, but may be increased in number relative to benign neoplasms
  2. Epithelial cells will have increased N:C ratio, moderate to marked anisokaryosis, nuclear molding, multiple large prominent nucleoli, abnormally shaped nuclei, and/or multinucleation +/- increased numbers of mitotic figures
• Special histochemical stains: Oil-Red-O or Sudan IV to demonstrate lipid droplets
• Immunohistochemistry: Cytokeratin positive; CAM 5.2 positive; vimentin negative

 

DIFFERENTIAL DIAGNOSIS:

Benign mixed tumor

• Complex adenoma – similar benign epithelial and myoepithelial components, but lacks mesenchymal component
• Carcinoma arising in benign mixed tumor – a benign mixed tumor with focal or multifocal areas of pleiomorphism and increased mitotic rate in the luminal epithelial cell population 
  1. Cases of carcinoma arising in benign mixed tumors are reported to follow a less aggressive disease course relative to solid carcinomas or comedocarcinoma (Seung et al., J Comp Pathol, 2021)
• Mixed carcinoma – mixed tumor with diffusely malignant epithelial component and benign myoepithelial component; lacks evidence of a pre-existing benign mixed tumor
• Carcinosarcoma – malignant epithelial and mesenchymal components +/- benign or malignant myoepithelial component

 

Lipid-rich carcinoma

• Liposarcoma - cytokeratin negative, CAM 5.2 negative, vimentin positive
• Spindle cell carcinoma - rare in dogs; composed of cytokeratin positive spindle cells that form solid cellular areas occasionally with intermixed tubules
• Squamous cell carcinoma - solid sheets and cords of cells with areas of squamous differentiation
• Mucinous carcinoma - rare in dog and cat; may be simple or complex with abundant mucin production
• Glycogen-rich carcinomas can occur in dogs, and should be distinguished from lipid-rich carcinomas through histochemical stains for glycogen which is PAS+, diastase-labile (Muscatello et al., Vet Pathol, 2021)

 

REFERENCES:

1. Allison RW, Walton RM. Subcutaneous Glandular Tissue: Mammary, Salivary, Thyroid, and Parathyroid. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:103-108. 
2. Brunetti B, Bacci B, Angeli C, et al. p53, ER, and Ki67 Expression in Canine Mammary Carcinomas and Correlation With Pathological Variables and Prognosis. Vet Pathol. 2021;58(2):325-331.
3. Canadas A, França M, Pereira C, et al. Canine Mammary Tumors: Comparison of Classification and Grading Methods in a Survival Study. Vet Pathol. 2019;56(2):208-219.
4. Foster RA. Female reproductive system and mammae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6^th ed. St. Louis, MO: Elsevier; 2017:1191-1192.
5. Goldschmidt MH, Pena L, Rasotto R, Zappulli V. Classification and grading of canine mammary tumors. Vet Pathol. 2011;48(1):117-131.
6. Goldschmidt MH, Pena L, Zappulli V. Tumors of the Mammary Gland. In: Meuten DJ, ed. Tumors in Domestic Animals. 5^th ed. Ames, IA: John Wiley & Sons, Inc.; 2017:751.
7. Hassan BB, Elshafae SM, Supsavhad W, et al. Feline Mammary Cancer. Vet Pathol. 2017;54(1):32-43.
8. Muscatello LV, Papa V, Millanta F, Sarli G, Bacci B, Cenacchi G, Poli A, Giudice C, Brunetti B. Canine Mammary Carcinoma With Vacuolated Cytoplasm: Glycogen-Rich Carcinoma, a Histological Type Distinct From Lipid-Rich Carcinoma. Vet Pathol. 2021;58(1):63-70.
9. Otsuka N, Hirata A, Yonemaru K, Goto M, Murakami M, Sakai H. Benign Mixed Mammary Tumour with Hepatoid Gland Differentiation in a Dog. J Comp Pathol. 2022;197:35-39.
10. Rasotto R, Berlato D, Goldschmidt MH, et al. Prognostic Significance of Canine Mammary Tumor Histologic Subtypes: An Observational Cohort Study of 229 Cases. Vet Pathol. 2017;54(4):571-578.
11. Rogez B, Pascal Q, Bobillier A, et al. CD44 and CD24 Expression and Prognostic Significance in Canine Mammary Tumors. Vet Pathol. 2019;56(3):377-388.
12. Schlafer DH, Foster RA. Female genital system. In: Maxie MG, ed. Jubb, Kennedy, Palmer’s Pathology of Domestic Animals. Vol 3. Philadelphia, PA: Elsevier Saunders; 2016:460-463.
13. Seung BJ, Cho SH, Kim SH, Bae MK, Lim HY, Kwak SW, Sur JH. Impact of Histological Subtype on Survival in Canine Mammary Carcinomas: a Retrospective Analysis of 155 Cases. J Comp Pathol. 2021;186:23-30. 
14. Solano-Gallego L, Masserdotti C. Chapter 13: Reproductive System. In: Raskin RE, Meyer DJ, & Boes KM eds. Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2022:446-450.

 

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